Evaluation of the therapeutic effect of radiotherapy on cervical cancer using magnetic resonance imaging

Int. J. Radiation Oncology Biol. Phys., Vol. 45, No. 3, pp. 639 – 644, 1999 Copyright © 1999 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/99/$–see front matter

PII S0360-3016(99)00228-X

CLINICAL INVESTIGATION

Cervix

EVALUATION OF THE THERAPEUTIC EFFECT OF RADIOTHERAPY ON CERVICAL CANCER USING MAGNETIC RESONANCE IMAGING KAZUO HATANO, M.D.,* YUICHI SEKIYA, M.D.,* HITOSHI ARAKI, M.D.,* MITSUHIRO SAKAI, M.D.,* TAKASHI TOGAWA, M.D.,* YUICHIRO NARITA, PH.D.,* YOSHIHISA AKIYAMA, PH.D.,* SHINJIRO KIMURA, M.D.,† AND HISAO ITO, M.D.† *Division of Radiation Oncology, Chiba Cancer Center, Chiba City, Japan; and †Department of Radiology, School of Medicine, Chiba University, Chiba City, Japan Purpose: This study was performed to evaluate magnetic resonance imaging (MRI) in determining the therapeutic effect of radiotherapy (RT) on cervical cancer. Methods and Materials: Serial MRI studies were performed in 42 patients with predominantly advanced cervical cancer before, during, and after radiotherapy. Patients underwent external irradiation combined with highdose-rate intracavitary (HDR) brachytherapy. T-2 weighted spin-echo pulse sequences with long repetition and echo times were used at a field strength of 1.5 T. Multiple punch biopsies of the cervix were obtained from the high-signal intensity area in all patients at the same time as the MRI. Result: In biopsies performed immediately after RT, no residual tumors were found in 36 patients (86%); in 6 patients, residual tumors were observed. The simultaneous MRI study demonstrated no high-signal intensity on T2-weighted images in 28 patients. A high-signal area was observed in 14 patients, and this disappeared 3 months after RT in 8 patients with a negative histological study. The sensitivity, specificity, and accuracy of MRI studies at 3 months after RT were 100%. When the relationship between reduction of tumor volume at 30 Gy and local tumor control was analyzed, every patient with a reduction under 30% gained local control. Also, patients with no residual tumors 3 months after RT gained local control. Conclusion: MRI studies performed at 30 Gy of external irradiation and 3 months after RT were predictive factors of local control. © 1999 Elsevier Science Inc. Magnetic resonance imaging, Radiotherapy, Cervical cancer, Therapeutic effect.

cult, and a biopsy is often required to resolve the question. Recent reports on MRI indicate tumor recurrence can usually be differentiated from radiation fibrosis on the basis of signal intensity (3, 8). Typically, fibrosis has low-signal intensity on both T1- and T2-weighted images. Tumors, however, exhibit a high-signal intensity on T2-weighted (T2W) images. Unfortunately, the inflammation and edema associated with acute radiation change (which may persist for up to 18 months) may also have high-signal intensity on T2W images, sometimes leading to an incorrect diagnosis (8, 9). In this study, the findings of MRI were compared with cytology and histopathology before and after radiotherapy. The purpose of this study was to determine whether MRI could provide accurate information to evaluate residual tumors after radiotherapy.

INTRODUCTION In cervical cancer, a bimanual rectovaginal examination has been the only method available to diagnose the size and degree of invasion of the cancer. The accuracy of this clinical method depends on the experience of the physician, and is often inaccurate with regard to variables such as the parametrium, pelvic sidewall, and tumor size. After its introduction, computed tomography (CT) imaging was applied to the evaluation of cervical cancer. However, CT is of limited value in differentiating cervical tumors from normal tissues. Magnetic resonance imaging (MRI), however, can better delineate cervical tumor size, location, and extension into adjacent structures with its superior soft tissue definition and multiplanar scanning capacities (1). Whereas CT staging decisions correlate with actual surgical findings 60 –70% of the time (2, 3), MRI provides accurate staging information in 70 –90% of cases (4 –7). The clinical distinction between residual or recurrent tumors and post-treatment fibrosis may be extremely diffi-

METHODS AND MATERIALS Forty-two patients with cervical cancer, seen at our department between December 1994 and April 1997, and

Reprint requests to: Kazuo Hatano, M.D., Division of Radiation Oncology, Chiba Cancer Center, 666-2 Nitona-cho, Chuo-ku, Chiba 260-0801 Japan. Tel: 043-264-5431; Fax: 043-262-8680; E-mail: [email protected]

Presented at the 40th Annual ASTRO Meeting, Phoenix, AZ, October 25–29, 1998. Accepted for publication 3 June 1999. 639

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Table 1. Patient characteristics n Age (years) Pathology

62.3 ⫾ 7.5 Squamous cell carcinoma Adenocarcinoma

FIGO stage IB IIB IIIB IVA Radiation Therapy Whole pelvis 30 Gy 40 Gy RALS device 60 Co 192 Ir

40 2 5 13 20 4 38 4 16 26

undergoing radical radiotherapy (RT), were enrolled in the study. Characteristics of the study patients are summarized in Table 1. The patient population was aged between 33–90 years (mean ⫾ standard deviation, 62.3 ⫾ 7.5). Forty patients had squamous cell carcinoma and 2 had adenocarcinoma. Patients were initially evaluated by physical and pelvic examination, routine blood count, chemistry profile, chest X-ray, and i.v. pyelogram. Multiple punch biopsies of the cervix were obtained from all patients, and dilatation was frequently performed at the time of intracavitary brachytherapy. MRIs were performed on all patients. The treatment modality was not modified by the findings of these tests. Patients were staged by the staff of the Department of Gynecology according to the FIGO system. Five patients were classified as Stage Ib, 13 as Stage IIb, 20 as Stage IIIb, and 4 as Stage IVa. Patients were treated with a combination of external irradiation and high-dose-rate (HDR) intracavitary brachytherapy (RALS). Whole pelvic irradiation was delivered using conventional anterior-posterior parallel opposed fields. Following 30 – 40 Gy, a central shield was inserted to avoid an overdose of radiation to the bladder and rectum, then an additional 10 –20 Gy was delivered to the pelvis until the dose reached 50 Gy. This treatment portal pattern was applied to all Stage Ib-IVa patients, and was unchanged throughout the study period. HDR intracavitary irradiation was initiated in all patients after 30 Gy of external irradiation, using a Toshiba HDR system (RALS) or a microSelectron HDR system. The treatment system contained a 60 Co (67 GBq) source (RALS) or an 192Ir (730 GBq) source (microSelectron) in tandem and each colpostat. The uterine applicator was inserted to reach the uterine fundus. The tandem source could be moved either automatically stepwise at a distance of 2.5–10 mm from the uterine fundus through to the external os of the cervix. Henschke-type vaginal applicators, which were separated from the tandem, were then placed in the vaginal fornix, and the vagina was packed with gauze. Orthogonal x-ray pictures were taken

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for dose calculation using a Modulex system for RALS or the three-dimensional system, “PLATO” for microSelectron. Total doses of 24 Gy were given, with a dose per fraction of 6 Gy once a week. The dose administered by brachytherapy was evaluated at point A. The brachytherapy doses were not changed throughout the various clinical stages. Patients were followed-up periodically by the staff in our departments. The median follow-up in surviving patients was 27.4 months (maximum 43 months, minimum 12 months). The information was available to all patients. MRI studies were performed on all patients before radiotherapy, at 30 Gy of external irradiation, immediately after radiotherapy, and 1, 3, and 6 months after radiotherapy. MRI was performed using a 1.5 Tesla scanner (Signa 1.5T, GE). All images were reconstructed in a 256 ⫻ 256 matrix with pixel size of 1.7-mm square, averaging the data from two acquisitions. Scanning sequences were as follows: a coronal locator with T1-weighted (T1W) images was generated; then 20 contiguous 5-mm-thick axial T2W images were obtained, using a spin-echo (SE) sequence with a repetition time of 4,000 ms and echo times of 40 and 80 ms (SE 4000/40/80): axial SE 500/40. T1W was then generated in the same fashion, and finally, sagittal SE 4000/40/80 T2W images were obtained, again in 5-mm-thick contiguous slices. The area to be covered extended from 1 cm above the top of the uterus to 2 cm below the cervical os. Laterally, the images extended to the sagittal images to include the whole disease area, that is, to the pelvic sidewalls. When the MRI study was performed, a small tampon (cotton ball) was inserted into the vagina to dilate the vaginal wall. On MRI, cervical cancer appears as a high-signal intensity mass on T2W images, and can be distinguished from the normal low-signal intensity cervical stroma (6, 7, 10). The maximum diameters of the cancer mass were measured using the sagittal and axial images and the volume was calculated with the formula d1 ⫻ d2 ⫻ d3 ⫻ ␲/6 for the ellipsoid, where d represents three orthogonal diameters. The effect of radiotherapy was evaluated immediately following, and then 1, 3, and 6 months after RT. When no high-signal intensity was observed on the T2W images, it was judged as “no residual tumor” (complete response: CR). Multiple punch biopsies and cytology of the cervix were obtained from the high-signal intensity area from all patients at the same time as the MRI imaging, and the relationship between histological evaluation and MRI imaging was determined. RESULTS Relationship between MRI and histological studies Multiple punch biopsies and cytology of the cervix were performed immediately after RT. They showed no residual tumors in 36 patients (86%). Six patients were diagnosed with residual tumors by histological study. The MRI study, performed at the same time as the histological study, demonstrated no high-signal intensity on the T2W images in 28

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Fig. 1. A 46 year-old woman with stage 11B squamous cell cervical cancer (a) Before radiation therapy, a large hyperintense cervical tumour was seen (arrows). (b) AE the time of the 1st. RALS, the tumor decreased in size (arrowheads). (c) Immediately after radiation therapy, no residual tumor was seen.

patients (Fig. 1). Fourteen patients had high-signal areas and were suspected to have residual tumors (Fig. 2). Table 2 shows the relationship between the histological and MRI studies. Patients were classified into 4 groups according to the MRI and histological findings immediately after RT. These were: true negative (TN), true positive (TP), false negative (FN), and false positive (FP). Both studies (MRI and histological) suggested no residual tumors in 28 patients (TN) and residual tumors in 6 patients (TP). Eight patients (19%) demonstrated high-signal intensity on the T2W images and were suspected as having residual tumors, despite there being no residual tumor according to histological findings (FP). None of the patients’ histological studies suggested a residual tumor; but whose MRI showed no

residual tumor (FN). MRI study was completely matched with the histological findings in 34 of 42 patients (81%). These findings did not change 1 month after RT. Six patients demonstrated residual tumors by both histological and MRI studies. Three of these six patients underwent radical surgery at 1–2 months after RT and were confirmed as having residual tumors. Two of these three patients who underwent surgery developed distant metastases and died during the follow-up period, and another patient died of carcinomatous peritonitis 3 months after RT. One patient with a residual tumor, but without surgery, was given additional intracavitary brachytherapy (6 Gy). Both studies performed 1 month after additional treatment showed no residual tumor in this patient (Fig. 3), and she is

Fig. 2. A 73-year-old woman with Stage IIB squamous cell cervical cancer. (a) Before radiation therapy, a hyperintense cervical tumor was seen (arrows). (b) After radiation therapy, a hyperintense residual tumor on the posterior of the cervix was suspected (arrow heads). (c) Three months after radiation therapy, the hyperintense tumor disappeared.

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Table 2. Correlation of MRI study and histological finding Total

TN Hist

TP MRI

(⫺) Immediately after RT 1 month after RT 3 month after RT 6 month after RT

42 42 39 35

(⫺)

Hist

MRI

(⫹)

28 (67) 28 (67) 37 (95) 34 (97)

FP

(⫹) 6 (14) 6 (14) 2 (5) 1 (3)

Hist

FN MRI

(⫺)

(⫹) 8 (19) 8 (19) — —

Hist

MRI

(⫹)

(⫺) — — — —

TN:True Negative, TP:True Positive, FP:Fals Positive, FN:Fals Negative Hist:Histology, RT:Radiation Therapy

still alive without recurrence. The remaining two patients with residual tumors refused further treatment. These two patients died of carcinomatous peritonitis and lung metastases with local tumor growth at 5– 6 months after RT. Although eight patients were suspected of having residual tumors by MRI studies at the completion of RT, the histological findings were negative (FP). These high-signal intensity masses disappeared within 3 months after RT. One patient died of cerebral bleeding 7 months after RT, with no local recurrence. MRI studies were performed on 39 patients 3 months after RT (3 were excluded because of surgical extirpation). Thirty-seven patients showed no high-signal intensity on T2W images (TN) (Fig. 2) (Table 2). Two patients who had residual tumors and refused additional treatment had highsignal intensity areas and positive histological findings (TP). MRI study 3 months after RT coincided completely with the histological findings in all patients (100%). These findings did not change 6 months after RT. Of 37 patients with a complete response to both the histological and MRI studies, 3 patients developed distant metastases and died. They had no recurrence of the primary lesion at disease. The remaining 34 patients were alive and underwent histological and MRI studies every 3– 6 months. Neither local recurrence nor distant metastasis was found during the follow-up period.

The sensitivity, specificity, and accuracy of MRI studies were calculated, and are shown in Table 3. The indexes immediately after RT were 100%, 78%, and 81%, respectively. MRI studies performed 1 month after RT showed the same values as those immediately after RT. Three months after RT, these indexes were determined in 39 patients. All indexes improved and were 100%. Six months after RT, 4 patients died because of distant metastases; however, these indexes were the same as at 3 months. The patients who showed no high-signal intensity on the T2W images 3 months after RT did not have any local recurrence during the follow-up period.

Changes in tumor volume Changes in tumor volume during and after RT are shown in Table 4. Tumor volume before treatment (mean 84.3 cm3, range 2.7–554 cm3) decreased to 29% (59.3– 0%) at 30 Gy of external irradiation. Comparing the reduction in the tumor volume between the TP, TN, and FP groups, it was largest in the TN group. However, the difference was not significant, because of a large standard deviation. Initial tumor volumes were reduced to under 30% at 30 Gy of external irradiation in 37 patients. The relationship between reduction in tumor volume at 30 Gy and local tumor control was determined. Every patient with tumor volume reduction

Fig. 3. A 47-year-old woman with Stage IIB squamous cell cervical cancer. (a) Before radiation therapy, a hyperintense cervical tumor was seen (arrows). (b) One month after radiation therapy, hyperintense residual tumor on the right side of the cervix was suspected (arrow heads), and included positive histological findings. (c) One month after boost RALS of 6 Gy, the hyperintense tumor disappeared.

Evaluation of radiotherapy effect on cervical cancer with MRI

Table 3. Accuracy of MRI

Immediately after RT 1 month after RT 3 month after RT 6 month after RT

Sensitivity (%)

Specificity (%)

Accuracy (%)

100 100 100 100

78 78 100 100

81 81 100 100

RT:Radiation Therapy

under 30% achieved local control during the follow-up period. The reduction of tumor volume at 30 Gy was one of the predictive factors for local control by RT. Immediately after RT, no residual tumors were found in 28 patients, using both MRI and histological studies. These patients also achieved local control. On the other hand, 6 of 9 patients who had tumors larger than 5% of the initial volume immediately after RT had persistent tumors and poor prognoses. DISCUSSION Bimanual pelvic examination is commonly used to estimate primary tumor size and the extent of its involvement in cervical cancer prior to treatment. Similarly, tumor response in patients undergoing RT for cervical cancer, and the adjustments and planned reductions in the radiation field throughout the course of treatment, are usually based on palpatory findings. This is, however, a subjective method. It has interobserver variability and may not always enable optimal evaluation (11–13), particularly with quantitative assessment. Furthermore, the clinical distinction between residual and recurrent tumors and post-treatment fibrosis may be extremely difficult. Biopsy is often required to resolve the question. It is easy to obtain the appropriate specimens for the histological study from the surface of the cervix; however, it is difficult to obtain them from the deep area of the cervix and the parametrium. Both CT and MRI complement the clinical evaluation, providing information about areas that are clinically inaccessible, and allowing better overall evaluation of the patient. The introduction of CT has resulted in a substantial improvement in the spatial

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resolution and anatomical detail of the pelvic organs, making CT the most readily and routinely used modality for pelvic imaging, particularly for nodal involvement (14 –16). With its multiplanar capability, distinctive tissue characteristics, and exquisite anatomical detail, MRI has been reported to be superior to CT in the evaluation of pelvic anatomy and malignancies of the uterus. On MRI, cervical cancer appears as a high-signal intensity mass on T2W images, and can be distinguished from the normal lowsignal intensity cervical stroma (6, 7, 10). MRI differentiation between tumors and fibrosis can be achieved with a high degree of accuracy. Furthermore, the strength of MRI is its ability to directly visualize the tumor, therefore allowing measurement of its size. Excellent correlation of tumor size between MRI and pathology has been reported (4). MRI is the most appropriate study for the evaluation of the postirradiation pelvis when searching for suspected residual tumors or recurrence of cervical carcinoma (17). In this study, 8 of 36 patients with negative histological findings demonstrated a high-signal intensity area on T2W images performed immediately after radiotherapy, and were suspected as having residual tumors. This MRI finding disappeared 3 months after radiotherapy. There was, however, a discrepancy between the MRI and the histological findings. Typically, fibrosis has a low-signal intensity on both T1W and T2W images. On the other hand, tumors exhibit a high-signal intensity on T2W images. However, the inflammation and edema associated with acute radiation change may also demonstrate a high-signal intensity on T2W images, sometimes leading to an incorrect diagnosis (8, 9). This acute radiation change subsided within 3 months of RT in this study. Flueckiger et al. noted that all tumors regressed completely within 6 months of radiotherapy, showing a characteristic drop in relative signal intensity following radiotherapy. This decline was most precipitous during the first 3 months and was almost complete at 6 months (18). In the current study, the high-signal area disappeared more quickly, as compared to Flueckiger’s study, possibly due to differences in methods of RT and obtaining MRIs. This suggests that it is useful to obtain MRIs 3 months after RT, to evaluate the effect of RT. Several prognostic factors, including clinical evaluation

Table 4. Change of tumor volume

No. of patients Before treatment 30 Gy of Ext. RT Immediately after RT 1 month after RT 3 month after RT

True positive

True negative

False positive

Hist(⫹), MRI(⫹)

Hist(⫺), MRI(⫺)

Hist(⫺), MRI(⫹)

6 187.0 cm3 32.7%* 13%

28 (136–278) (39–30.2) (34.9–1.3)

— —

87.6 cm3 14.9% 0% 0% 0%

8 (2.7–554) (29.5–0)

58.6 cm3 24.8% 5.2% 2.2% 0%

(21.7–193.2) (30–8.4) (11.1–3.0) (4.4–1.3)

Hist:Histology, Ext.RT:External Radiation Therapy, RT:Radiation Therapy * % of tumor volume compared to that of before treatment

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(e.g., patient age and Karnofsky Performance Status) histological findings (tumor grade), and morphological features, such as tumor size (diameter), location, depth of stromal invasion, local tumor extension, and lymph node metastasis, have been shown to affect the therapeutic outcome (19, 20). In this study, tumor size reduction measured with MRI was thought to be one of the predictive factors for local control. Patients with tumor sizereduction under 30% at 30 Gy of external irradiation had good local control. Some authors established a relationship between short-term response and long-term prognosis with low-dose-rate brachytherapy (21–24). Applying HDR brachytherapy, a close association was also observed between the absence of a clear-cut complete response within 2 months of the completion of treatment and higher recurrence or shorter survival time (25). Indeed, such a relationship has generally also been observed in squamous cell carcinomas of the head and neck (26, 27). These clinical studies evaluated tumor response after RT, utilizing MRI to measure tumor size, allowing an earlier

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tumor response evaluation, for example, during RT. We recommend using MRI before radiotherapy and at 30 Gy of external irradiation. This information is very useful for predicting better local control. The goal of radiation therapy is to deliver the maximum possible dose to the tumor without damaging normal cells. However, adjacent tissue is invariably exposed, and radiation-induced tissue changes may occur. CT imaging during intracavitary gynecological brachytherapy has been shown to be a valuable tool for accurately estimating the radiation doses to organs such as the bladder and rectum. However, it is difficult to delineate the tumor from the surrounding normal tissues. MRI can better delineate cervical tumor size, location, and extension into adjacent structures, with its superior soft tissue definition and multiplanar scanning capacities (1). In this study, we discussed the superiority of MRI in evaluating the effect of radiotherapy. We are now developing this method to apply MRI to calculate the most appropriate dose distribution with brachytherapy.

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